E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of levodopa-responsive Parkinson's subjects with severe motor fluctuations. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10013113 |
E.1.2 | Term | Disease Parkinson's |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study will be to provide further evidence of the long-term safety and tolerability of levodopa-carbidopa intestinal gel (Duodopa®) over 6-12-months in subjects with advanced Parkinson’s Disease (PD) and severe motor-fluctuations who have not had optimal response to oral levodopa-carbidopa treatment. Additional supportive evidence for efficacy will be assessed in the treatment of severe motor-fluctuations, dyskinesia and mobility. |
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E.2.2 | Secondary objectives of the trial |
A secondary objective is to assess the long-term maintenance of efficacy. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Diagnosis of idiopathic Parkinson’s disease according to the United Kingdom Parkinson’s Disease Society (UKPDS) Brain Bank Criteria with the diagnosis made at least 2 years prior to enrollment in the study. 2. The subject’s Parkinson’s disease must be the levodopa-responsive type as judged by the investigator; additionally, subjects will need to demonstrate severe motor fluctuations in spite of individually optimized treatment, and where other therapy options beside oral treatment are indicated. 3. Subjects have had optimal treatment with available PD medication as defined by local standards of care and, based upon the judgment of the investigator, are judged inadequately controlled on this optimized treatment. 4. Presence of a recognizable “off” and “on” state (motor fluctuations) as confirmed by diary at baseline (diary measurements performed for the three days preceding the baseline visit). 5. Subjects or subject’s proxy/caretaker must be able to keep a subject diary of “off” time. 6. Minimum “off” time must be approximately 3 hours per day as estimated by the investigator. 7. The subject must be able to understand the nature of the study and must provide written informed consent prior to the conduct of any study procedures (including any changes occurring in the subject’s current therapeutic regimen). 8. Subjects must be able to speak, read, understand and possess the ability to respond to and follow simple instructions in their native language and/or in English. All required documents, including the informed consent, will be translated into the native language as appropriate. 9. Male or female subjects aged at least 30 years 10. Females who are not breast-feeding or are of non-childbearing potential may be enrolled. All females of child bearing potential must have a negative serum beta-human chorionic gonadotropin (β-HCG) test prior to study entry. Non-childbearing is defined as: -last natural menstruation at least 24 months prior to baseline, or -surgically sterilized (i.e. bilateral tubal sterilization) at least three months prior to baseline, or -total hysterectomy at least three months prior to baseline 11. A female subject of child-bearing potential may be enrolled provided that she is maintained on a medically acceptable method of birth control. |
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E.4 | Principal exclusion criteria |
Subjects meeting any of the exclusion criteria listed below either at screening and/or baseline must be excluded from participation in the study.
1. Diagnosis is unclear or a suspicion of other Parkinsonian syndromes exists, such as secondary Parkinsonism (caused by drugs, toxins, infectious agents, vascular disease, trauma, brain neoplasm), Parkinson-plus syndromes (e.g., multiple system atrophy, progressive supranuclear palsy) or the other neurodegenerative diseases; 2. Subjects who have undergone surgery for the treatment of PD (e.g., pallidotomy, deep brain stimulation, fetal tissue transplantation); 3. Subjects with any neurological deficit that might interfere with the study assessments (e.g. hemiparesis); and/or any subjects who have had a stroke in the last two years; 4. Treatment with prohibited medications 5. Known hypersensitivity to levodopa, carbidopa or radiopaque material; 6. Contraindications to levodopa, such as narrow angle glaucoma, hyperthyroidism, pheochromocytoma, Cushing’s syndrome and history of malignant melanoma; 7. Subjects who are experiencing sleep attacks or who exhibit clinically significant impulsive behavior (e.g. pathological gambling, hypersexuality). 8. Current diagnosis or history of drug or alcohol abuse (Diagnostic and Statistical Manual of Mental Disorders [DSM]-IV-TR criteria) within 12 months prior to screening visit; 9. Current primary psychiatric diagnosis of acute psychotic disorder or other primary psychiatric diagnoses, such as bipolar disorder or major depressive disorder (DSM-IV-TR criteria); 10. Psychiatric, neurological or behavioral disorders that may interfere with the ability of subjects to give informed consent, or interfere with the conduct or interpretation of the study; troublesome hallucinations would also be included under this category; 11. Alzheimer’s disease; or other significant cognitive impairment or dementia (defined as [MMSE] <24). 12. Clinically significant abnormal laboratory data (e.g., aspartate aminotransferase [AST] or alanine aminotransferase [ALT] greater than three times the upper limit of normal) or any abnormal laboratory value that could interfere with the assessment of safety in the judgment of the investigator; 13. Current evidence of clinically significant hematological, autoimmune, endocrine, cardiovascular, renal or gastrointestinal disorder that would possibly interfere with the subject’s participation in the study (e.g., treated, controlled and thus stable hypertension is not considered an exclusion criterion); 14. A history of, or a known current gastrointestinal, liver, kidney or other known condition, which may interfere with the absorption, distribution, metabolism or excretion of the study medication and/or assessments, or interfere with the insertion of the tubing system (e.g., subjects who have undergone gastric or intestinal surgery other than, for instance, appendectomy or cholecystectomy); 15. Any malignant disease or a history of neoplasms, other than carcinoma in situ of the cervix or basal cell carcinoma of the skin, within the past five years prior to screening; Additionally, subjects with prostate cancer may be considered for enrollment in the study following a comprehensive assessment and a discussion between the Investigator and the Medical Monitor regarding the appropriateness of the subject for the study; 16. Medical, laboratory or surgical issues deemed by the investigator to be clinically significant; 17. A planned surgical procedure scheduled for when a subject would be participating in the study (subjects may later be considered for inclusion following full recuperation from the surgical procedure). 18. Exposure to any investigational drug within 30 days prior to baseline; 19. Prior exposure to levodopa-carbidopa gel; 20. Uncooperative attitude or reasonable likelihood for non-compliance with the protocol; 21. Site personnel and their immediate families defined as spouse, parent, child, grandparent or grandchild; or 22. Subjects who will not provide written informed consent for participation in the study. 23. Subjects for whom placement of a PEG-J tube for levodopa/carbidopa intestinal gel treatment is contraindicated, or that the subject would be considered a high risk for the PEG-J procedure, according to the gastroenterologist’s evaluation. Contraindications for PEG-J tube placement include, but are not limited to, the following conditions: pathological changes of the gastric wall, inability to bring the gastric wall and abdominal wall together, blood coagulation disorders, peritonitis, acute pancreatitis, and paralytic ileus. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety and tolerability will be assessed by changes from baseline in: - Physical examination including weight - Vital signs: systolic/diastolic blood pressure, pulse rate and temperature including orthostatic vital signs (supine and standing [after two minutes]) - Clinical laboratory assessments including biochemistry (sodium [Na], potassium [K], chloride [Cl], blood urea nitrogen [BUN], bicarbonate, creatinine [Cr], creatine kinase [CK], glucose, gamma-glutamyl transferase [GGT], calcium [Ca], aspartate transaminase [AST], alanine transaminase [ALT], alkaline phosphatase [ALP], total bilirubin, lactate dehydrogenase [LDH], total protein, uric acid, total cholesterol, triglycerides, and blood alcohol), hematology (complete blood count [CBC] with differential, red blood cell [RBC], platelet counts, mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH] and mean corpuscular hemoglobin concentration MCHC) and urinalysis (dipstick). Thyroid function studies ((including TSH, and free T4 from serum) will be performed only at screening and pregnancy testing (serum β-HCG) will be performed on women of childbearing potential at screening and every 12 weeks thereafter. - Resting 12-lead electrocardiogram (ECG) - Concomitant medication use - Adverse Event monitoring (including sleep attacks, for the development of melanoma or impulsive behavior) - Monitoring complications of the infusion device - Abnormal Involuntary Movement Scale (AIMS) - Premature study terminations
Efficacy will be assessed by: - Change from baseline in mean daily “off” time (hours), based on a self-administered home diary assessment of motor state on three consecutive days at multiple intervals. - Change from baseline in the diary based assessment of “on” time with troublesome dyskinesia, and “on” time without troublesome dyskinesia - Clinical Global Impression-Improvement (CGI-I) scores - Unified Parkinson’s Disease Rating Scale (UPDRS) total score and sub-scores of parts I-III. Practically defined “off” time (pre am dose) and best “on” time (1-2 hours post dose) and Part IV (subscore Dyskinesia items) - Total score Parkinson’s Disease Questionnaire-39 (PDQ-39)
Pharmacokinetics: Whole blood samples (6 mL per sample) will be obtained for the determination of plasma concentrations of levodopa.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Information not present in EudraCT |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Information not present in EudraCT |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 52 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |